Elucidation of molecular epidemiology and pathophysiology of acquired sideroblastic anemia

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K08314
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Tohoku University
• Principal Investigator: Fujiwara Tohru 東北大学, 大学病院, 講師 (60333796)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 後天性鉄芽球性貧血

Outline of Final Research Achievements

Acquired sideroblastic anemia, characterized by bone marrow ring sideroblasts (RS), is predominantly associated with myelodysplastic syndrome (MDS). Although somatic mutations in splicing factor 3b subunit 1 (SF3B1), which is involved in the RNA splicing machinery, are frequently found in MDS-RS, the detailed mechanism contributing to RS formation is unknown. To explore the mechanism, we established human umbilical cord blood-derived erythroid progenitor-2 (HUDEP-2) cells stably expressing SF3B1K700E. SF3B1K700E expressing cells showed higher proportion of RS than the control cells along with erythroid differentiation. In SF3B1K700E expressing cells, ABCB7 and ALAS2, known causative genes for congenital sideroblastic anemia, were downregulated. ABCB7-knockdown HUDEP-2 cells revealed an increased frequency of RS formation along with erythroid differentiation. Finally, RNA-seq analysis of MDS clinical samples demonstrated decreased expression of ABCB7 by the SF3B1 mutation.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

後天性鉄芽球性貧血の代表であるMDS-RSにおける環状鉄芽球形成機序について、先天性と共通の分子基盤が存在する可能性があるが、この点について包括的な解析を行った報告は国内外を含め認められない。本分子基盤の一端を明らかにしたことは、MDS-RSのみならず鉄芽球性貧血全体の病態の理解に繋がるだけでなく、MDS-RSへの新規治療法の開発にも繋がる可能性がある。また、本研究成果が赤芽球におけるヘム・鉄代謝に関する未知の生理的機構の解明に繋がる可能性もある。